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Vitamin E Deficiency and Oxidative Status are Associated with Prediabetes in Apparently Healthy Subjects
Archives of Medical Research 48 (2017) 257e262
ORIGINAL ARTICLE
Vitamin E Deficiency and Oxidative Status are Associated with Prediabetes in Apparently Healthy Subjects Gabriela Rodrıguez-Ramırez,a Luis E. Simental-Mendıa,b Manuela de la A. Carrera-Gracia,a and Martha-Angelica Quintanar-Escorzaa b
a Facultad de Medicina y Nutricion, Universidad Juarez del Estado de Durango, Durango, Dgo., Mexico Unidad de Investigacion Biomedica del Instituto Mexicano del Seguro Social en Durango, Durango, Dgo., Mexico
Received for publication September 2, 2016; accepted March 27, 2017 (ARCMED-D-16-00532).
Background. Previous studies have indicated that vitamin E deficiency and oxidative stress affect the beta cell function. Hence, the aim of this study was to determine the association between vitamin E deficiency and oxidative status with prediabetes in apparently healthy subjects. Methods. Apparently healthy men and women aged 18e65 years were enrolled in a casecontrol study. Individuals with new diagnosis of prediabetes were considered as cases and compared with a control group of individuals with normal glucose tolerance. Smoking, alcohol intake, pregnancy, diabetes, kidney disease, liver disease, cardiovascular disease, malignancy, glucocorticoid treatment and consumption of lipid-lowering drugs, antioxidants and vitamin supplements were exclusion criteria. Vitamin E deficiency was defined by serum levels of a-tocopherol !11.6 mmol/L, oxidative status was assessed by total antioxidant capacity and lipid peroxidation, and prediabetes was considered by the presence of impaired fasting glucose and/or impaired glucose tolerance. Results. A total of 148 subjects were allocated into the case (n 5 74) and control (n 5 74) groups. The frequency of vitamin E deficiency was higher in the case group (41.8%) compared with the control group (35.1%), p 5 0.03. The logistic regression analysis adjusted by age, waist circumference and body mass index, revealed a significant association between vitamin E deficiency (OR 3.23; 95% CI: 1.34e7.79, p 5 0.009), lipoperoxidation (OR 2.82; CI 95%: 1.42e5.59, p 5 0.003) and total antioxidant capacity (OR 0.93; CI 95%: 0.90e0.96, p !0.001) with prediabetes. Conclusions. Results of the present study suggest that both vitamin E deficiency and oxidative status are associated with prediabetes in apparently healthy subjects. Ó 2017 IMSS. Published by Elsevier Inc. Key Words: Vitamin E deficiency, Oxidative status, Prediabetes, Lipoperoxidation, Antioxidant capacity.
Introduction Prediabetes is a previous stage to diabetes which represents a high risk for subsequent development of cardiovascular disease (1). Furthermore, the American Diabetes Association has indicated that around 70% of individuals with prediabetes eventually progress to diabetes (2). The World
Address reprint requests to: Luis E. Simental-Mendıa, MD, PhD, Canoas 100, Col. Los Angeles, 34067, Durango, Dgo., Mexico; Phone/Fax: (þ52) (618) 812-0997; E-mail: [email protected].
Health Organization, in 2004, reported a global prevalence for prediabetes of 33% and estimated more than 470 million people by 2030 (3). Hence, if current trends continue, an increased rate for prediabetes is expected worldwide. Accordingly, it is mandatory to implement effective recommendations based on primary prevention of diabetes including programs aimed at the high-risk population such as those with prediabetes (4,5). Vitamin E, a general term including a-, b-, d-, and g-forms of tocopherol and tocotrienol chemical classes, is a lipid-soluble vitamin with lipid antioxidant properties (6).
0188-4409/$ - see front matter. Copyright Ó 2017 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2017.03.018
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Rodrıguez-Ramırez et al./ Archives of Medical Research 48 (2017) 257e262
In this regard, previous studies suggest that vitamin E status may be involved in glucose metabolism independently of its antioxidant mechanism (7). Moreover, reduced insulin secretion and decreased antioxidant capacity were observed in animal models with induced vitamin E deficiency (8). In crosssectional studies, plasma tocopherol concentrations have been inversely correlated with insulin resistance (9). A prospective cohort found an increased risk of type 2 diabetes in individuals with low vitamin E concentrations (10). Some studies have reported that vitamin E supplementation improves insulin action and decreases oxidative stress enhancing the function of pancreatic beta cells (11,12). However, the vitamin E status in the prediabetic condition state, characterized by insulin resistance and beta cell dysfunction (13), has been poorly studied. Therefore, the objective of this study was to determine the association between vitamin E deficiency and oxidative status with prediabetes in apparently healthy subjects.
Materials and Methods Previous protocol approval by the Mexican Social Security Institute Research Committee and after obtaining the written informed consent, a case-control study was conducted. Eligible subjects, apparently healthy men and women aged 18e65 years, were recruited from the general population of Durango, a city in northern Mexico. All participants underwent anthropometric measurements, routine blood chemistry, and a standardized oral glucose tolerance test. The oral glucose tolerance test was performed in the morning following an overnight 10 h fast; 150 mL of a solution containing 75 g of dextrose was given orally. Venous blood samples were obtained at fasting and 2 h post-load (14). Individuals with new diagnosis of prediabetes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT] or both) were considered as cases and compared with a control group of subjects exhibiting normal glucose tolerance (NGT). Subjects of both groups were enrolled from the same socio-cultural and economic background. A standardized interview, clinical examination, and laboratory tests were performed to carefully determine the presence of smoking, alcohol intake equal or greater than 20 g per day, pregnancy, diabetes, kidney disease, liver disease, cardiovascular disease, malignancy, glucocorticoid treatment and consumption of lipid-lowering drugs, antioxidant supplements and vitamin complexes containing vitamin E, which were exclusion criteria. Definitions Vitamin E deficiency was defined by serum levels of atocopherol !11.6 mmol/L (15), oxidative status was assessed by total antioxidant capacity and lipid peroxidation
(malondialdehyde concentration), and prediabetes was considered by the presence of either IFG (fasting glucose concentration $100 and !126 mg/dL), IGT (2 h postload glucose $140 and !200 mg/dL) or IFG þ IGT (14). NGT was defined by fasting glucose concentration !100 mg/dL and 2 h post-load glucose !140 mg/dL. Insulin resistance was determined using the product of fasting triglycerides and glucose levels (TyG) calculated by the Ln (Fasting triglycerides [mg/dL] fasting glucose [mg/dL]/2) (16). Measurements In the standing position and fasting conditions, waist circumference (WC), weight and height were measured using a fixed scale with a stadiometer (Tanita TBF-215, Tokyo, Japan) with the subjects in light clothing and without shoes. The body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. The WC was measured to the nearest centimeter using a flexible tape; the anatomical landmarks were the midway between the lowest portion of the rib cage and the superior border of the iliac crest (17). The technique for measurement of blood pressure was the recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (18). Assays A whole blood sample was collected from the antecubital vein after 10e12 h overnight fasting. The serum glucose was measured using the glucose-oxidase method with intraand inter-assay variation coefficients of 1.1 and 1.5%. Total cholesterol and triglycerides were enzymatically measured using spectrophotometric methods (19). HDL-cholesterol (HDL-C) fraction was obtained after precipitation by phosphotungstic reagent and then determined in the supernatant. The intra- and inter-assay coefficients of variation were 1.8 and 2.6% for total cholesterol, 1.7 and 3.1% for triglycerides, and 1.3 and 2.6% for HDL-C. LDL-cholesterol fraction was calculated by Friedewald equation (20). Alpha-tocopherol levels were determined by spectrofluorometry (Shimadzu RF-5301PC) using the following wavelengths: excitation at 292 nm, emission at 400 nm, and reading at 325 nm. (21). The total antioxidant capacity was measured in plasma spectrophotometrically by ABTS/peroxidase system. The produced amount of ABTS þ was determined by absorbance at 450 nm (22). Evaluation of lipid peroxidation was performed in whole blood by spectrophotometry measuring the thiobarbituric acid reactive species (TBARS). The reaction results in malondialdehyde, a red pigment determined at 532 nm (23).
Vitamin E, Oxidative Status and Prediabetes
Figure 1. Study participant flow diagram.
Statistical Analysis Differences between the groups were estimated using Student t test (ManneWhitney U test for skewed data) for numerical variables, and the c2 test for categorical variables. A multiple logistic regression analysis was used to compute the odds ratio (OR) between vitamin E deficiency and oxidative status (independent variables) and prediabetes (dependent variable). An additional logistic regression analysis adjusted by age, WC, and BMI was conducted in order to control the potential confounders. A 95% confidence interval (95% CI) and p value !0.05 defined statistical significance. Data were analyzed using the statistical package SPSS 15.0. (SPSS Inc., Chicago IL). Results A total of 247 subjects were screened; of these, 99 (40%) individuals were excluded because they did not meet the
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inclusion criteria or by the presence of exclusion criteria such as smoking, alcohol intake, diabetes, and consumption of lipid-lowering drugs, antioxidants and vitamins. Finally, 148 subjects (107 women and 41 men) with average age of 40.9 12.1 years were enrolled; of them, 74 (29.9%) were allocated into the case group and 74 (29.9%) in the control group (Figure 1). Clinical and biochemical characteristics of the study population are summarized in Table 1; subjects in the case group were older and had higher WC, body fat percentage, BMI, systolic and diastolic blood pressure and higher fasting glucose, post-load glucose, TyG index, triglyceride and total cholesterol levels than individuals in the control group. In the case group, diagnosis of IFG, IGT and IFG þ IGT was established in 40 (16.1%), 15 (6.0%) and 19 (7.6%) subjects, respectively. The frequency of vitamin E deficiency in the study population was 38.5%. In this context, individuals in the case group show a significantly higher frequency of vitamin E deficiency than those in the control group (41.8 vs. 35.1%, p 5 0.03). With respect to serum levels of atocopherol, the cases exhibited a lower concentration compared with the controls (Table 2). Regarding oxidative status parameters, the subjects in the case group had a significantly higher malondialdehyde levels as well as lower concentration of total antioxidant capacity than those in the control group (Table 2). The unadjusted multiple logistic regression analysis showed a significant association between vitamin E deficiency, lipidperoxidation and total antioxidant capacity (independent variables) with prediabetes (dependent variable). In order to control the potential confounders, an additional logistic regression analysis adjusted by age, WC and BMI was performed indicating that vitamin E deficiency
Table 1. Clinical and biochemical characteristics of the target population
Age (years) Women, n (%) Waist circumference (cm) Body fat (%) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting glucose (mg/dL) Post-load glucose (mg/dL) Triglycerides (mg/dL)b TyG index Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL)
Screening
Cases
Controls
n [ 247
n [ 74
n [ 74
p
41.7 11.9 170 (68.8) 94.2 15.8 36.1 8.9 29.7 6.0 117.0 16.3 74.9 10.2 100.8 23.0 127.2 55.6 153.0 (99e222) 4.82 0.36 197.3 41.9 47.9 14.4 110.8 38.8
45.2 10.9 53 (71.6) 99.9 14.9 39.2 7.7 31.3 5.5 119.7 16.5 77.2 10.1 104.0 7.7 131.3 32.0 192.0 (134e285) 4.98 0.33 212.0 41.4 49.0 15.1 112.8 44.7
36.5 11.7 54 (72.9) 88.0 13.7 33.9 8.5 28.0 4.9 113.7 14.5 72.3 9.6 89.3 5.6 102.3 23.9 111.0 (86e173) 4.65 0.29 190.4 44.6 46.4 11.5 114.2 37.9
!0.001* 0.85** !0.001* !0.001* !0.001* 0.02* 0.003* !0.001* !0.001* !0.001a !0.001 0.003* 0.244* 0.840*
Values are expressed as mean standard deviation unless otherwise is indicated. p value between Cases and Controls; *p value estimated using Student t test; **p value estimated using c2 test. a Value estimated using U de Mann Whitney test. b Median (25e75 interquartile range); TyG index, Ln (fasting triglycerides [mg/dL] fasting glucose [mg/dL]/2).
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Table 2. Parameters of vitamin E and oxidative status of the population in study Cases n [ 74
Controls n [ 74
p
Alpha-tocopherol 13.3 (8.6e18.0) 13.8 (11.5e19.1) 0.03 (mmol/L)* Vitamin E deficiency, 31 (41.8) 26 (35.1) 0.03 n (%)** 1.87 1.30 1.25 0.46 !0.001 Malondialdehyde (nmol MDA/mL)a Total antioxidant capacity 0.23 0.04 0.27 0.01 !0.001 (trolox equivalent mM)a *p Value estimated using U de Mann Whitney test vales in median (Percentile 25e75); **p Value estimated using c2 test. a p Value estimated using Student t test.
(OR 3.23; 95% CI: 1.34e7.79, p 5 0.009), malondialdehyde levels (OR 2.82; CI 95%: 1.42e5.59, p 5 0.003), and total antioxidant capacity (OR 0.93; CI 95%: 0.90e0.96, p !0.001) remained independently associated with prediabetes (Table 3).
Discussion The findings of our study show that both vitamin E deficiency and oxidative status, assessed by lipid peroxidation and total antioxidant capacity, are associated with prediabetes in apparently healthy subjects. Most studies evaluating vitamin E deficiency have been conducted in developing countries, focusing especially on high-risk populations. Furthermore, these studies have considered different cutoff points, study design and target populations resulting in prevalence of vitamin E deficiency ranging from 20e90% (24). However, to the best of our knowledge, the role of vitamin E deficiency in prediabetes has not been previously investigated; hence, our results provides novel data in this field. Several studies exploring the role of vitamin E on hyperglycemia have been performed in type 2 diabetes population (25). In this regard, a prospective cohort study found a strong independent association between low plasma vitamin E levels and increased risk of diabetes (26). Table 3. Association between vitamin E deficiency and oxidative status with pre-diabetes OR (95% CI) Vitamin E deficiency Malondialdehyde levels Total antioxidant capacity
2.08 3.23 3.02 2.82 0.93 0.93
(1.04e4.18) (1.34e7.79) (1.61e5.66) (1.42e5.59) (0.91e0.96) (0.90e0.96)
p 0.03 0.009a 0.001 0.003a !0.001 !0.001a
OR, odds ratio; CI 95%, 95% confidence interval. a Logistic regression analysis adjusted by age, waist circumference and body mass index.
Besides, inverse association between plasma a-tocopherol concentration and fasting glucose levels was observed in women (27). Also, vitamin E intake has been inversely related to glycated hemoglobin in non-diabetic population (28). Another study reported that vitamin E supplementation decreased fasting plasma glucose and improved insulin resistance in overweight subjects, although these changes were transient (7). Thus, our results are in agreement with the above mentioned studies. Nonetheless, the biological effects of tocopherols on glucose metabolism are not well-known. In this context, there is evidence indicating that chronic oxidative stress induces a defective insulin gene expression by dysfunction of two important transcription factors, PDX-1 and MafA, resulting in the inactivation of insulin promoter (29,30). Hence, this abnormal insulin mRNA expression impacts on beta cell function reducing insulin content and insulin secretion (31). In addition, the excessive levels of reactive oxygen species may induce an increased islet apoptosis causing a decreased beta cell mass (32). However, it has been demonstrated that negative effects of oxidative stress on the pancreatic beta cells can be partially prevented by antioxidant agents (33,34). Therefore, a-tocopherol, a potent antioxidant, may exert a potential beneficial impact enhancing the antioxidant enzyme activity, which is responsible for protecting pancreatic islets from oxidative damage. Nevertheless, further clinical trials evaluating the vitamin E effect on prediabetes condition are needed in order to confirm this hypothesis. Moreover, also it has been hypothesized that oxidative stress is associated with prediabetes phenotypes (35). Thus, increased oxidative stress in the prediabetic state has been indicated in our study by the reduced total antioxidant capacity and elevated malondialdehyde levels, which is consistent with results from previous studies (35e37). In this regard, Su et al. (38) found a higher concentration of malondialdehyde compared with NGT group. Our results are in agreement with these findings, which may be related to the increased BMI and WC, characteristics of individuals with prediabetes, given that visceral obesity has been associated with systemic oxidative stress (39,40). Therefore, it has been suggested that earlier changes in the antioxidant status, characteristic of the initial phase of oxidative stress, could occur before the onset of diabetes (41). Also, in consistency with our outcomes, some studies (42,43) have reported a reduced total antioxidant activity in prediabetics compared with NGT subjects reflecting an increased oxidative stress in prediabetic stage which might predict the development of type 2 diabetes (41). There are some limitations which deserve be mentioned. First, the cross-sectional design does not allow establishing with certainty the temporality of the cause-effect relationship. Second, insulin levels were not measured; nonetheless, since insulin resistance is a hallmark of prediabetic state, a higher insulin concentration is expected in the case group compared with the control group as suggested by the
Vitamin E, Oxidative Status and Prediabetes
TyG index, a reliable indicator of insulin resistance. Finally, we did not evaluate the daily food intake and physical activity; nevertheless, since subjects were included from the same socio-cultural and economic background, it is expected that both diet and physical activity were distributed similarly in the study groups. On the other hand, the strengths of our study include the appropriate and representative sample size from the general population that gives adequate power to statistical analysis, and inclusion of individuals with newly diagnosis of prediabetes without prior treatment, which minimizes the risk of bias in the analysis of cross-sectional studies. Conclusion In conclusion, the results of the present study suggest that both vitamin E deficiency and oxidative status are associated with prediabetes in apparently healthy subjects. Conflict of Interest Authors have none conflict of interest declared within the manuscript. References 1. Ford ES, Zhao G, Li C. Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence. J Am Coll Cardiol 2010;55:1310e1317. 2. Tabak AG, Herder C, Rathmann W, et al. Prediabetes: a high-risk state for diabetes development. Lancet 2012;379:2279e2290. 3. Wang H, Shara NM, Calhoun D, et al. Incidence rates and predictors of diabetes in those with prediabetes: the Strong Heart Study. Diabetes Metab Res Rev 2010;26:378e385. 4. Lindstr€ om J, Neumann A, Sheppard KE, et al. Take action to prevent diabetesethe IMAGE toolkit for the prevention of type 2 diabetes in Europe. Horm Metab Res 2010;42(Suppl 1):S37eS55. 5. Paulweber B, Valensi P, Lindstr€om J, et al. A European evidencebased guideline for the prevention of type 2 diabetes. Horm Metab Res 2010;42(Suppl 1):S3eS36. 6. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Crit Rev Clin Lab Sci 2008;45:417e450. 7. Manning PJ, Sutherland WH, Walker RJ, et al. Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects. Diabetes Care 2004;27:2166e2171. 8. Asayama K, Kooy NW, Burr IM. Effect of vitamin E deficiency and selenium deficiency on insulin secretory reserve and free radical scavenging systems in islets: decrease of islet manganosuperoxide dismutase. J Lab Clin Med 1986;107:459e464. 9. Facchini FS, Humphreys MH, DoNascimento CA, et al. Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols. Am J Clin Nutr 2000;72:776e779. 10. Salonen JT, Nyyss€ onen K, Tuomainen TP, et al. Increased risk of noninsulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men. BMJ 1995;311:1124e1127. 11. Paolisso G, D’Amore A, Giugliano D, et al. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and noninsulin-dependent diabetic patients. Am J Clin Nutr 1993;57: 650e656. 12. Caballero B. Vitamin E improves the action of insulin. Nutr Rev 1993; 51:339e340.
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13. Kanat M, Mari A, Norton L, et al. Distinct b-cell defects in impaired fasting glucose and impaired glucose tolerance. Diabetes 2012;61: 447e453. 14. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26:3160e3167. 15. Garcia-Bailo B, El-Sohemy A, Haddad PS, et al. Vitamins D, C, and E in the prevention of type 2 diabetes mellitus: modulation of inflammation and oxidative stress. Biologics 2011;5:7e19. 16. Simental-Mendıa LE, Rodrıguez-Moran M, Guerrero-Romero F. The product of fasting glucose and triglycerides as surrogate for identifying insulin resistance in apparently healthy subjects. Metab Syndr Relat Disord 2008;6:299e304. 17. Guerrero-Romero F, Rodrıguez-Moran M, Perez-Fuentes R, et al. Prediabetes and its relationship with obesity in Mexican adults: The Mexican Diabetes Prevention (MexDiab) Study. Metab Syndr Relat Disord 2008;6:15e23. 18. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute;National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42: 1206e1252. 19. Allain CC, Poon LS, Chan CS, et al. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470e475. 20. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499e502. 21. Pastor Ferrer MC, Codoceo Alquinta R, Deulofeu Piquet R, et al. Procedimiento recomendado para la determinacion de a-tocoferol en suero. Quımica Clınica 1996;15:445e449. 22. Miller NJ, Rice-Evans C, Davies MJ. A new method for measuring antioxidant activity. Biochem Soc Trans 1993;21:95S. 23. Visioli F, Colombo C, Galli C. Oxidation of individual fatty acids yields different profiles of oxidation markers. Biochem Biophys Res Commun 1998;245:487e489. 24. Dror DK, Allen LH. Vitamin E deficiency in developing countries. Food Nutr Bull 2011;32:124e143. 25. Yl€onen K, Alfthan G, Groop L, et al. Dietary intakes and plasma concentrations of carotenoids and tocopherols in relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study. Am J Clin Nutr 2003;77:1434e1441. 26. Pazdro R, Burgess JR. The role of vitamin E and oxidative stress in diabetes complications. Mech Ageing Dev 2010;131:276e286. 27. Ble-Castillo JL, Carmona-Dıaz E, Mendez JD, et al. Effect of atocopherol on the metabolic control and oxidative stress in female type 2 diabetics. Biomed Pharmacother 2005;59:290e295. 28. Boeing H, Weisgerber UM, Jeckel A, et al. Association between glycated hemoglobin and diet and other lifestyle factors in a nondiabetic population: cross-sectional evaluation of data from the Potsdam cohort of the European Prospective Investigation into Cancer and Nutrition Study. Am J Clin Nutr 2000;71:1115e1122. 29. Olson LK, Sharma A, Peshavaria M, et al. Reduction of insulin gene transcription in HIT-T15 beta cells chronically exposed to a supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression. Proc Natl Acad Sci U S A 1995;92: 9127e9131. 30. Harmon JS, Stein R, Robertson RP. Oxidative stress-mediated, posttranslational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells. J Biol Chem 2005; 280:11107e11113. 31. Tanaka Y, Tran PO, Harmon J, et al. A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity. Proc Natl Acad Sci U S A 2002;99:12363e12368.
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ORIGINAL ARTICLE
Vitamin E Deficiency and Oxidative Status are Associated with Prediabetes in Apparently Healthy Subjects Gabriela Rodrıguez-Ramırez,a Luis E. Simental-Mendıa,b Manuela de la A. Carrera-Gracia,a and Martha-Angelica Quintanar-Escorzaa b
a Facultad de Medicina y Nutricion, Universidad Juarez del Estado de Durango, Durango, Dgo., Mexico Unidad de Investigacion Biomedica del Instituto Mexicano del Seguro Social en Durango, Durango, Dgo., Mexico
Received for publication September 2, 2016; accepted March 27, 2017 (ARCMED-D-16-00532).
Background. Previous studies have indicated that vitamin E deficiency and oxidative stress affect the beta cell function. Hence, the aim of this study was to determine the association between vitamin E deficiency and oxidative status with prediabetes in apparently healthy subjects. Methods. Apparently healthy men and women aged 18e65 years were enrolled in a casecontrol study. Individuals with new diagnosis of prediabetes were considered as cases and compared with a control group of individuals with normal glucose tolerance. Smoking, alcohol intake, pregnancy, diabetes, kidney disease, liver disease, cardiovascular disease, malignancy, glucocorticoid treatment and consumption of lipid-lowering drugs, antioxidants and vitamin supplements were exclusion criteria. Vitamin E deficiency was defined by serum levels of a-tocopherol !11.6 mmol/L, oxidative status was assessed by total antioxidant capacity and lipid peroxidation, and prediabetes was considered by the presence of impaired fasting glucose and/or impaired glucose tolerance. Results. A total of 148 subjects were allocated into the case (n 5 74) and control (n 5 74) groups. The frequency of vitamin E deficiency was higher in the case group (41.8%) compared with the control group (35.1%), p 5 0.03. The logistic regression analysis adjusted by age, waist circumference and body mass index, revealed a significant association between vitamin E deficiency (OR 3.23; 95% CI: 1.34e7.79, p 5 0.009), lipoperoxidation (OR 2.82; CI 95%: 1.42e5.59, p 5 0.003) and total antioxidant capacity (OR 0.93; CI 95%: 0.90e0.96, p !0.001) with prediabetes. Conclusions. Results of the present study suggest that both vitamin E deficiency and oxidative status are associated with prediabetes in apparently healthy subjects. Ó 2017 IMSS. Published by Elsevier Inc. Key Words: Vitamin E deficiency, Oxidative status, Prediabetes, Lipoperoxidation, Antioxidant capacity.
Introduction Prediabetes is a previous stage to diabetes which represents a high risk for subsequent development of cardiovascular disease (1). Furthermore, the American Diabetes Association has indicated that around 70% of individuals with prediabetes eventually progress to diabetes (2). The World
Address reprint requests to: Luis E. Simental-Mendıa, MD, PhD, Canoas 100, Col. Los Angeles, 34067, Durango, Dgo., Mexico; Phone/Fax: (þ52) (618) 812-0997; E-mail: [email protected].
Health Organization, in 2004, reported a global prevalence for prediabetes of 33% and estimated more than 470 million people by 2030 (3). Hence, if current trends continue, an increased rate for prediabetes is expected worldwide. Accordingly, it is mandatory to implement effective recommendations based on primary prevention of diabetes including programs aimed at the high-risk population such as those with prediabetes (4,5). Vitamin E, a general term including a-, b-, d-, and g-forms of tocopherol and tocotrienol chemical classes, is a lipid-soluble vitamin with lipid antioxidant properties (6).
0188-4409/$ - see front matter. Copyright Ó 2017 IMSS. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.arcmed.2017.03.018
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Rodrıguez-Ramırez et al./ Archives of Medical Research 48 (2017) 257e262
In this regard, previous studies suggest that vitamin E status may be involved in glucose metabolism independently of its antioxidant mechanism (7). Moreover, reduced insulin secretion and decreased antioxidant capacity were observed in animal models with induced vitamin E deficiency (8). In crosssectional studies, plasma tocopherol concentrations have been inversely correlated with insulin resistance (9). A prospective cohort found an increased risk of type 2 diabetes in individuals with low vitamin E concentrations (10). Some studies have reported that vitamin E supplementation improves insulin action and decreases oxidative stress enhancing the function of pancreatic beta cells (11,12). However, the vitamin E status in the prediabetic condition state, characterized by insulin resistance and beta cell dysfunction (13), has been poorly studied. Therefore, the objective of this study was to determine the association between vitamin E deficiency and oxidative status with prediabetes in apparently healthy subjects.
Materials and Methods Previous protocol approval by the Mexican Social Security Institute Research Committee and after obtaining the written informed consent, a case-control study was conducted. Eligible subjects, apparently healthy men and women aged 18e65 years, were recruited from the general population of Durango, a city in northern Mexico. All participants underwent anthropometric measurements, routine blood chemistry, and a standardized oral glucose tolerance test. The oral glucose tolerance test was performed in the morning following an overnight 10 h fast; 150 mL of a solution containing 75 g of dextrose was given orally. Venous blood samples were obtained at fasting and 2 h post-load (14). Individuals with new diagnosis of prediabetes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT] or both) were considered as cases and compared with a control group of subjects exhibiting normal glucose tolerance (NGT). Subjects of both groups were enrolled from the same socio-cultural and economic background. A standardized interview, clinical examination, and laboratory tests were performed to carefully determine the presence of smoking, alcohol intake equal or greater than 20 g per day, pregnancy, diabetes, kidney disease, liver disease, cardiovascular disease, malignancy, glucocorticoid treatment and consumption of lipid-lowering drugs, antioxidant supplements and vitamin complexes containing vitamin E, which were exclusion criteria. Definitions Vitamin E deficiency was defined by serum levels of atocopherol !11.6 mmol/L (15), oxidative status was assessed by total antioxidant capacity and lipid peroxidation
(malondialdehyde concentration), and prediabetes was considered by the presence of either IFG (fasting glucose concentration $100 and !126 mg/dL), IGT (2 h postload glucose $140 and !200 mg/dL) or IFG þ IGT (14). NGT was defined by fasting glucose concentration !100 mg/dL and 2 h post-load glucose !140 mg/dL. Insulin resistance was determined using the product of fasting triglycerides and glucose levels (TyG) calculated by the Ln (Fasting triglycerides [mg/dL] fasting glucose [mg/dL]/2) (16). Measurements In the standing position and fasting conditions, waist circumference (WC), weight and height were measured using a fixed scale with a stadiometer (Tanita TBF-215, Tokyo, Japan) with the subjects in light clothing and without shoes. The body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. The WC was measured to the nearest centimeter using a flexible tape; the anatomical landmarks were the midway between the lowest portion of the rib cage and the superior border of the iliac crest (17). The technique for measurement of blood pressure was the recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (18). Assays A whole blood sample was collected from the antecubital vein after 10e12 h overnight fasting. The serum glucose was measured using the glucose-oxidase method with intraand inter-assay variation coefficients of 1.1 and 1.5%. Total cholesterol and triglycerides were enzymatically measured using spectrophotometric methods (19). HDL-cholesterol (HDL-C) fraction was obtained after precipitation by phosphotungstic reagent and then determined in the supernatant. The intra- and inter-assay coefficients of variation were 1.8 and 2.6% for total cholesterol, 1.7 and 3.1% for triglycerides, and 1.3 and 2.6% for HDL-C. LDL-cholesterol fraction was calculated by Friedewald equation (20). Alpha-tocopherol levels were determined by spectrofluorometry (Shimadzu RF-5301PC) using the following wavelengths: excitation at 292 nm, emission at 400 nm, and reading at 325 nm. (21). The total antioxidant capacity was measured in plasma spectrophotometrically by ABTS/peroxidase system. The produced amount of ABTS þ was determined by absorbance at 450 nm (22). Evaluation of lipid peroxidation was performed in whole blood by spectrophotometry measuring the thiobarbituric acid reactive species (TBARS). The reaction results in malondialdehyde, a red pigment determined at 532 nm (23).
Vitamin E, Oxidative Status and Prediabetes
Figure 1. Study participant flow diagram.
Statistical Analysis Differences between the groups were estimated using Student t test (ManneWhitney U test for skewed data) for numerical variables, and the c2 test for categorical variables. A multiple logistic regression analysis was used to compute the odds ratio (OR) between vitamin E deficiency and oxidative status (independent variables) and prediabetes (dependent variable). An additional logistic regression analysis adjusted by age, WC, and BMI was conducted in order to control the potential confounders. A 95% confidence interval (95% CI) and p value !0.05 defined statistical significance. Data were analyzed using the statistical package SPSS 15.0. (SPSS Inc., Chicago IL). Results A total of 247 subjects were screened; of these, 99 (40%) individuals were excluded because they did not meet the
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inclusion criteria or by the presence of exclusion criteria such as smoking, alcohol intake, diabetes, and consumption of lipid-lowering drugs, antioxidants and vitamins. Finally, 148 subjects (107 women and 41 men) with average age of 40.9 12.1 years were enrolled; of them, 74 (29.9%) were allocated into the case group and 74 (29.9%) in the control group (Figure 1). Clinical and biochemical characteristics of the study population are summarized in Table 1; subjects in the case group were older and had higher WC, body fat percentage, BMI, systolic and diastolic blood pressure and higher fasting glucose, post-load glucose, TyG index, triglyceride and total cholesterol levels than individuals in the control group. In the case group, diagnosis of IFG, IGT and IFG þ IGT was established in 40 (16.1%), 15 (6.0%) and 19 (7.6%) subjects, respectively. The frequency of vitamin E deficiency in the study population was 38.5%. In this context, individuals in the case group show a significantly higher frequency of vitamin E deficiency than those in the control group (41.8 vs. 35.1%, p 5 0.03). With respect to serum levels of atocopherol, the cases exhibited a lower concentration compared with the controls (Table 2). Regarding oxidative status parameters, the subjects in the case group had a significantly higher malondialdehyde levels as well as lower concentration of total antioxidant capacity than those in the control group (Table 2). The unadjusted multiple logistic regression analysis showed a significant association between vitamin E deficiency, lipidperoxidation and total antioxidant capacity (independent variables) with prediabetes (dependent variable). In order to control the potential confounders, an additional logistic regression analysis adjusted by age, WC and BMI was performed indicating that vitamin E deficiency
Table 1. Clinical and biochemical characteristics of the target population
Age (years) Women, n (%) Waist circumference (cm) Body fat (%) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting glucose (mg/dL) Post-load glucose (mg/dL) Triglycerides (mg/dL)b TyG index Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL)
Screening
Cases
Controls
n [ 247
n [ 74
n [ 74
p
41.7 11.9 170 (68.8) 94.2 15.8 36.1 8.9 29.7 6.0 117.0 16.3 74.9 10.2 100.8 23.0 127.2 55.6 153.0 (99e222) 4.82 0.36 197.3 41.9 47.9 14.4 110.8 38.8
45.2 10.9 53 (71.6) 99.9 14.9 39.2 7.7 31.3 5.5 119.7 16.5 77.2 10.1 104.0 7.7 131.3 32.0 192.0 (134e285) 4.98 0.33 212.0 41.4 49.0 15.1 112.8 44.7
36.5 11.7 54 (72.9) 88.0 13.7 33.9 8.5 28.0 4.9 113.7 14.5 72.3 9.6 89.3 5.6 102.3 23.9 111.0 (86e173) 4.65 0.29 190.4 44.6 46.4 11.5 114.2 37.9
!0.001* 0.85** !0.001* !0.001* !0.001* 0.02* 0.003* !0.001* !0.001* !0.001a !0.001 0.003* 0.244* 0.840*
Values are expressed as mean standard deviation unless otherwise is indicated. p value between Cases and Controls; *p value estimated using Student t test; **p value estimated using c2 test. a Value estimated using U de Mann Whitney test. b Median (25e75 interquartile range); TyG index, Ln (fasting triglycerides [mg/dL] fasting glucose [mg/dL]/2).
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Table 2. Parameters of vitamin E and oxidative status of the population in study Cases n [ 74
Controls n [ 74
p
Alpha-tocopherol 13.3 (8.6e18.0) 13.8 (11.5e19.1) 0.03 (mmol/L)* Vitamin E deficiency, 31 (41.8) 26 (35.1) 0.03 n (%)** 1.87 1.30 1.25 0.46 !0.001 Malondialdehyde (nmol MDA/mL)a Total antioxidant capacity 0.23 0.04 0.27 0.01 !0.001 (trolox equivalent mM)a *p Value estimated using U de Mann Whitney test vales in median (Percentile 25e75); **p Value estimated using c2 test. a p Value estimated using Student t test.
(OR 3.23; 95% CI: 1.34e7.79, p 5 0.009), malondialdehyde levels (OR 2.82; CI 95%: 1.42e5.59, p 5 0.003), and total antioxidant capacity (OR 0.93; CI 95%: 0.90e0.96, p !0.001) remained independently associated with prediabetes (Table 3).
Discussion The findings of our study show that both vitamin E deficiency and oxidative status, assessed by lipid peroxidation and total antioxidant capacity, are associated with prediabetes in apparently healthy subjects. Most studies evaluating vitamin E deficiency have been conducted in developing countries, focusing especially on high-risk populations. Furthermore, these studies have considered different cutoff points, study design and target populations resulting in prevalence of vitamin E deficiency ranging from 20e90% (24). However, to the best of our knowledge, the role of vitamin E deficiency in prediabetes has not been previously investigated; hence, our results provides novel data in this field. Several studies exploring the role of vitamin E on hyperglycemia have been performed in type 2 diabetes population (25). In this regard, a prospective cohort study found a strong independent association between low plasma vitamin E levels and increased risk of diabetes (26). Table 3. Association between vitamin E deficiency and oxidative status with pre-diabetes OR (95% CI) Vitamin E deficiency Malondialdehyde levels Total antioxidant capacity
2.08 3.23 3.02 2.82 0.93 0.93
(1.04e4.18) (1.34e7.79) (1.61e5.66) (1.42e5.59) (0.91e0.96) (0.90e0.96)
p 0.03 0.009a 0.001 0.003a !0.001 !0.001a
OR, odds ratio; CI 95%, 95% confidence interval. a Logistic regression analysis adjusted by age, waist circumference and body mass index.
Besides, inverse association between plasma a-tocopherol concentration and fasting glucose levels was observed in women (27). Also, vitamin E intake has been inversely related to glycated hemoglobin in non-diabetic population (28). Another study reported that vitamin E supplementation decreased fasting plasma glucose and improved insulin resistance in overweight subjects, although these changes were transient (7). Thus, our results are in agreement with the above mentioned studies. Nonetheless, the biological effects of tocopherols on glucose metabolism are not well-known. In this context, there is evidence indicating that chronic oxidative stress induces a defective insulin gene expression by dysfunction of two important transcription factors, PDX-1 and MafA, resulting in the inactivation of insulin promoter (29,30). Hence, this abnormal insulin mRNA expression impacts on beta cell function reducing insulin content and insulin secretion (31). In addition, the excessive levels of reactive oxygen species may induce an increased islet apoptosis causing a decreased beta cell mass (32). However, it has been demonstrated that negative effects of oxidative stress on the pancreatic beta cells can be partially prevented by antioxidant agents (33,34). Therefore, a-tocopherol, a potent antioxidant, may exert a potential beneficial impact enhancing the antioxidant enzyme activity, which is responsible for protecting pancreatic islets from oxidative damage. Nevertheless, further clinical trials evaluating the vitamin E effect on prediabetes condition are needed in order to confirm this hypothesis. Moreover, also it has been hypothesized that oxidative stress is associated with prediabetes phenotypes (35). Thus, increased oxidative stress in the prediabetic state has been indicated in our study by the reduced total antioxidant capacity and elevated malondialdehyde levels, which is consistent with results from previous studies (35e37). In this regard, Su et al. (38) found a higher concentration of malondialdehyde compared with NGT group. Our results are in agreement with these findings, which may be related to the increased BMI and WC, characteristics of individuals with prediabetes, given that visceral obesity has been associated with systemic oxidative stress (39,40). Therefore, it has been suggested that earlier changes in the antioxidant status, characteristic of the initial phase of oxidative stress, could occur before the onset of diabetes (41). Also, in consistency with our outcomes, some studies (42,43) have reported a reduced total antioxidant activity in prediabetics compared with NGT subjects reflecting an increased oxidative stress in prediabetic stage which might predict the development of type 2 diabetes (41). There are some limitations which deserve be mentioned. First, the cross-sectional design does not allow establishing with certainty the temporality of the cause-effect relationship. Second, insulin levels were not measured; nonetheless, since insulin resistance is a hallmark of prediabetic state, a higher insulin concentration is expected in the case group compared with the control group as suggested by the
Vitamin E, Oxidative Status and Prediabetes
TyG index, a reliable indicator of insulin resistance. Finally, we did not evaluate the daily food intake and physical activity; nevertheless, since subjects were included from the same socio-cultural and economic background, it is expected that both diet and physical activity were distributed similarly in the study groups. On the other hand, the strengths of our study include the appropriate and representative sample size from the general population that gives adequate power to statistical analysis, and inclusion of individuals with newly diagnosis of prediabetes without prior treatment, which minimizes the risk of bias in the analysis of cross-sectional studies. Conclusion In conclusion, the results of the present study suggest that both vitamin E deficiency and oxidative status are associated with prediabetes in apparently healthy subjects. Conflict of Interest Authors have none conflict of interest declared within the manuscript. References 1. Ford ES, Zhao G, Li C. Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence. J Am Coll Cardiol 2010;55:1310e1317. 2. Tabak AG, Herder C, Rathmann W, et al. Prediabetes: a high-risk state for diabetes development. Lancet 2012;379:2279e2290. 3. Wang H, Shara NM, Calhoun D, et al. Incidence rates and predictors of diabetes in those with prediabetes: the Strong Heart Study. Diabetes Metab Res Rev 2010;26:378e385. 4. Lindstr€ om J, Neumann A, Sheppard KE, et al. Take action to prevent diabetesethe IMAGE toolkit for the prevention of type 2 diabetes in Europe. Horm Metab Res 2010;42(Suppl 1):S37eS55. 5. Paulweber B, Valensi P, Lindstr€om J, et al. A European evidencebased guideline for the prevention of type 2 diabetes. Horm Metab Res 2010;42(Suppl 1):S3eS36. 6. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Crit Rev Clin Lab Sci 2008;45:417e450. 7. Manning PJ, Sutherland WH, Walker RJ, et al. Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects. Diabetes Care 2004;27:2166e2171. 8. Asayama K, Kooy NW, Burr IM. Effect of vitamin E deficiency and selenium deficiency on insulin secretory reserve and free radical scavenging systems in islets: decrease of islet manganosuperoxide dismutase. J Lab Clin Med 1986;107:459e464. 9. Facchini FS, Humphreys MH, DoNascimento CA, et al. Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols. Am J Clin Nutr 2000;72:776e779. 10. Salonen JT, Nyyss€ onen K, Tuomainen TP, et al. Increased risk of noninsulin dependent diabetes mellitus at low plasma vitamin E concentrations: a four year follow up study in men. BMJ 1995;311:1124e1127. 11. Paolisso G, D’Amore A, Giugliano D, et al. Pharmacologic doses of vitamin E improve insulin action in healthy subjects and noninsulin-dependent diabetic patients. Am J Clin Nutr 1993;57: 650e656. 12. Caballero B. Vitamin E improves the action of insulin. Nutr Rev 1993; 51:339e340.
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